1alpha-methyl-2-formyl-5alpha-androst-2-en-17-one and derivatives

ABSTRACT

1 X-METHYL-2-FORMYL-5X-ANDROST-2-EN-17-ONE AND ITS DERIVATIVES ARE PRODUCED FROM THE APPROPRIATE 1X-METHYL17B-HYDROXY-17X-(OPTIONALLY ALKYLATED)-5X-ANDROSTAN-3ONES AND ARE VALUABLE PHARMACOLOGICAL AGENTS AS IS EVIDENCED BY THEIR ANTI-ESTROGENIC, ANDROGENIC AND ANABOLIC ACTIVITIES.

United States Patent 7 3,657,289 1ct-METHYL-Z-FORMYL-Sot-ANDROST-Z-EN-17-0NE AND DERIVATIVES Paul D. Klimstra, Nortlrbrook, 111., assignor toG. D. Searle & Co., Chicago, Ill. N0 Drawing. Filed-Mar. 29, 1971, Ser.No. 129,115

1 Int. Cl. C07c 169/20 US. C]. 260-3973. 7 Claims ABSTRACT THEDISCLOSURE 1u-methyl-2-formyl-Se-andrQst-Z-en-17-one and its derivativesare produced from the appropriate lot-methyl- 175 hydroxy-17a-(optionally alkylated)-a-androstan-3- ones and are valuablepharmacological agents as is evidenced by their anti-estrogenic,androgenic and anabolic activities.

,The novel compounds of the present invention relate generally tosteroids of the androstane family. More specifically, this inventionrelates to- 1a-methy1-2-forrnyl- -5d-andr'ost-2en-17-one and itsderivatives, which compounds are illustrated by the structural formulabelow wherein is a' carbonyl radicalor a radical of the structuralformlua" "ice methylanilinomethylen)-5c -androstan 3 one. Reduction ofthe. 3-oxo substituent to the 3-hydroxy substituent is convenientlyaccomplished with a metallic hydride. For example, treating theaforementioned intermediate, 17,8- hydroxy 1amethyl-2-(N-methylanilinomethylen)-5eandrostan-3-one, with sodiumborohydride in methanol produces lwmethyl 2(N-methylanilinomethylen)-5:xandrostane-3,l7,8-diol. The diol then isconverted to the 2-formyl-A -17fl-o1 derivative with methanolic hydrogenchloride. Typically, 1a methyl 2 (Nmethylanilinomethylen)-5u-androstane-3,17,8-diol is contacted withhydrochloric acid in methanol to yield 1a-methyl-2-formyl-5u-androst-2-en-l7/8-o1. Additional products of the latter reaction are1a-methyl-l7u-(optionally alkylated)-2-methylen-5a-androstane-3,17fl-diols which are valuable intermediates forthe production of other pharmacological agents.

, Acylation of the 1ot-methy1-17a-(optionally alkylated)-2-formyl-5wandrost-Z-en-176-01 with an acid anhydride produces thel7fi-alkanoyl derivative. Acylation of the tertiary alcohol preferablyis accomplished under reflux conditions. The manufacture of thel7-ketone is accomplished by oxidation of 175-01 with chromic acid. Forexample, when la-methyl-2formyl-5u-andrOst-Z-en-17B- 01 is reacted withacetic anhydride in pyridine or 'with chromic acid, there is producedrespectively 1a-methyl-2- formyl-5u-androst-2-en-17B-ol 17-acetate andlot-methyl- Z-formyl-5a-androst-2-en-17-one.

The compounds of this invention exhibit useful pharmacological, e.g.anti-estrogenic, androgenic and anabolic, activity. The anti-estrogenicactivity is determined by an assay procedure described in US. Pat.3,539,558 and the anabolic and androgenic activity is determined by theprocedure described in US. Pat. 3,501,504.

The invention Will appear more fully from the examples which follow.These examples should not be construed as limiting the invention eitherin spirit or in scope as numerous modifications both in materials andmethods will be apparent to those skilled inv the art. Quantities ofmaterial are presented in parts by weight unless otherwise noted andtemperatures are given in degrees Centigrade 0.).

EXAMPLE 1 To a solution of 18 parts of l7fl-hydroxy-lu-methyl-5a-androstan-3-one in 527 parts of benzene is added 33.2 parts of ethylformate in one portion. That solution is stirred under a nitrogenatmosphere and 22.5 parts of a pounds of the:l7fi-hydroxy-l7oi-(optionally alkylated)- I iIa-methyI-Sa-androstan-3-one family. The method of manuiacturing thesestarting compounds is described'in Chem. and Pharm. Bull. Japan, 10, 386(1962). Contacting the appropriate 's'tartingcornpound with a strongbase, such as sodium hydride, in" the presence of an appropriate ester,such as ethyl formate, yields the corresponding sodium enolate whichsubsequently is converted to the enol by the addition of an aqueousmineral acid. For example, 'l7 8-hydroxy-la-methyl 5oz androstan-B-one,

when contacted with sodium hydride and ethyl formate and then treatedwithaqueous hydrochloric acid, is converted to1.7}8-hydroxy-1u-methyl-2-hydroxymethyIen-Saandrostan-3-one. The enolthen iscondensed in a basic medium, astfor examplewith N-methylanilinein methanol, to yield the N-methylanilinomethylene substitutedcondensation product. This type of reaction is illustrated by thereaction. of l7 3-hydroxy-lu-methyl-2-hydroxymethylen-5a-androstan-3-onewith N-methylaniline in 50% sodium hydride in oil dispersion is addedover a 5 minute period. The stirring is continued for 22 hours at roomtemperature, and then the solid material is removed by filtration,washed successively with benzene and hexane, and dried under reducedpressure at a temperature of about 60. The solid is added to 142 partsof hydrochloric acid in 600 parts of water with rapid stirringcontinuing for a period of about 15 minutes, thus forming a dark, highlyviscous material, which is separated by decantation. This material isdissolved in ethyl acetate, and that solution is filtered throguhdiatomaceous earth. The filtrate is washed with water and dried overanhydrous sodium sulfate and charcoal, and the solvent is removedyielding 17,9 hydroxy-1a-methyl-2-hydroXymethylen-5otandrostan-3-one asan oil,

EXAMPLE 2 A solution of 16 parts of l7fi-hydroxy-la-methyl-2-hydrOXymethylen-Su-androstan-3-one, 15.8 parts of fresh- 1y distilledN-methylaniline and 317 parts of methanol is methanol; thus affording17(3-hydroxy-Ia-methyI-Z-(N- refluxed for 4 hours. Then the solvent isremoved under reduced pressure, thus affording l7fi-hydroxy-lu-methyl-2-(N-methylanilinomethylen) 5u-androstan-3-one as an oil.

3 EXAMPLE 3 To 16 parts ofl7fl-hydroxy-la-methyl-2-(N-methylanilinomethylen)-u-androstan-3-onedissolved in 317 parts of methanol is added, with stirring and coolingin a water bath, a solution of parts of sodium borohydride in 50 partsof water. Stirring is continued for about 3 hours, and then water isadded. The solution is extracted with ether and the extracts are washedwith water and dried over anhydrous sodium sulfate and charcoal. Aftersolvent removal, la-methyl-Z-(N-methylanilinomethylen)- 5a-androstane-3,l7 3-diol remains as an oil.

EXAMPLE 4 -A solution of 16 parts ofla-methy1-2-(N-methylanilinomethylen)-5a-androstane-3,l7fi-diol and 317parts of methanol is treated with 29.6 parts of hydrochloric acid. Thesolution is stirred for /2 hour and kept at room temperature by theaddition of water. Additional water is added and then the solution isextracted with ether. The extracts are washed successively with waterand a 5% sodium "bicarbonate solution and dried over anhydrous sodiumsulfate and charcoal to yield, after solvent removal, a glass-likematerial. This material is taken up in benzene and chromatographed on asilica column to yield, after elution with ethyl acetate-benzenesolution, pure lumethyl-Z-formyl-Su-androst-Z-en-175-01. This compounddisplays a melting point at about 161-163 and an ultraviolet absorptionband at 231 millimicrons with a molecular extinction coefiicient ofabout 13,000. This compound further is represented by the followingstructural formula OH CH3 i ti... n rl Also afforded in the abovechromatographic fractionation is a mixture of1a-methyI-Z-methyIen-Sa-androstane-3a, 17fl-diol and1a-methyl-Z-methylen-Sa-androstane-B 18,1713- diol. These compounds arevaluable pharmacological, e.g. estrogenic and anti-fungal, agents.

EXAMPLE 5 A solution of 0.5 part of1a-methyl-Z-formyI-Sa-androst-2-en-17fl-ol, 5.5 parts of aceticanhydride, and 9.8 parts of pyridine is allowed to stand at roomtemperature for 48 hours. At the end of that time, methanol and waterare added and the solution is cooled to effect crys tallization. Thecrystals are collected, washed with water and dried in air to yield purela-methyl-2formyl-5aandrost-2-en-17fi-ol l7-acetate which exhibits anultraviolet maximum at about 231 millimicrons and a molecular extinctioncoefficient of about 12,600. This compound is represented by thefollowing structural formula EXAMPLE 6 When an equivalent quantity ofpropionic anhydride is substituted in the procedure of Example 5, thereis obtained la-methyl-2-formyl-5a-andrOst-Z-en-175-01 17 propionate.

4 EXAMPLE 7 EXAMPLE 8 A stirred solution of 18 parts of17,B-hydroxy-la,17adimethyl-Sa-androstan-3-one and 527 parts of benzeneis treated with 33.2 parts of ethyl formate, which is added in oneportion, and 22.5 parts of a 50% sodium hydride in oil dispersion, whichis added over a 5 minute period under a nitrogen atmosphere. The mixtureis continuously stirred at room temperature for 22 hours. The resultantsodium salt which forms is separated by filtration, Washed with benzeneand then hexane and dried at 50 under reduced pressure for 3 hours. Thesalt then is added to a stirred solution of 142 parts of hydrochloricacid and 1200 parts of water, and the precipitate is collected, washedwith water and air dried, thus yielding 17fl-h droxy-1a,17a-dimethyl 2hydroxymethylen-5a-andro stan-3-one. This compound is characterized byan ultraviolet absorption band at 286 millimicrons with a molecularextinction coefficient of 4200.

EXAMPLE 9 A solution of 18 parts of 17fi-hydroxy-le flet-dimethyl-2-hydroxymethylen-5a-androstan-3-one. 396 parts of methanol and 17.7parts of freshly distilled N-methylaniline is refluxed for 5 hours. Thesolution is cooled and the solvent is removed to produce crude 173-hydroxy-1a,17adimethyl-2-(N-methylanilinomethylen) 5 or androstan-3-one.

18 parts of the above crude product is dissolved in 356 parts ofmethanol, and to this solution is added, over a period of about 25minutes with stirring and with cooling in a cold water bath, 18 parts ofsodium borohydride dissolved in 50 parts of water. The solution isstirred at room temperature for an additional 2% hours and water isadded. Then the solution is extracted with ether and the extracts washedwith water and dried over anhydrous sodium sulfate and charcoal. Aftersolvent removal, 102,170:- dimethyl-Z-(N-methylanilinomethylen) 5aandrostane- 3,17p-diol remains as an oil.

EXAMPLE 10 To 18 parts of1a,17a-dimethyl-2-(N-methylanilinomethylen)-5a-androstane-3,l7B-diol in317 parts of methanol, cooled in a water bath is added, dropwise over a5 minute period and accompanied by stirring, 23.7 parts of hydrochloricacid. The solution is stirred for about 10 minutes. Then water is addedand the solution extracted with ether. The extracts are washed withwater and a 5% sodium bicarbonate solution and dried over anhydroussodium sulfate. Solvent is removed to leave an oil, which when taken upin benzene and chromatographed on silicon dioxide, yieldsla,l7a-dimethyl-2-formyl-5wandrost-2-en-l7fl-ol as an oil. The purematerial is obtained after recrystallization from a methanol-watersolution and is characterized by an ultraviolet absorption band at about231 millimicrons with a molecular extinction coeflicient of about 8200.This compound is represented by the following structural formulaAdditional fractions of the chromatographic process yield1a,l7a-dimethyl-2-methylen 501 androstane-35,17p-diol and 101,170:dimethyl-Z-methylen-Sa-androstane-3a,17pdiol as a mixture.

EXAMPLE 11 By substituting an equivalent quantity of 17a-ethyl-17B-hydroxy-IwmethyI-Sa-androstan-Zi-one as a starting material, and:otherwise following the procedure of Example 8, Example 9, and Example10, there is produced17a-ethyl-1m-rhethyl-Z-formyl-5a-androst-2-en-1713-01.

What is claimed is:

1. A compound of the formula 9 l C a wherein X is selected from thegroup consisting of a carbonyl radical and radicals of the formula 3. Asin claim 1, a compound of the formula O-(lower alkauoyl) 0113 i 4. As inclaim 1, a compound which is 1a-methyl-2-formyl-5a-androst-2-en-1718-01.

5. As in claim 1, a compound which is hz-methyl-Z-formyl-5u-androst-2-en-17 3-01 17-acetate.

6. As in claim 1, a compound which is 1a-methyl-2-formyI-Sm-andrOst-Z-en-17-one.

7. As in claim 1, a compound which is1a,17a-dimethyl-2-formyl5a-androst-2-en-175-01.

References Cited Orr et al.: J. Med. Chem. 6, p. 166-73 (1963). Counsellet al.: J. Med. Chem. 6, pp. 736-38 (1963).

0 HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 260397.4, 999

